Genetic Variant NM_004755.4:c.458A>T (chr14-90947487-T-A) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 3P and 4B. PM2PP3BS2

The NM_004755.4(RPS6KA5):c.458A>T(p.Glu153Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E153A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RPS6KA5
NM_004755.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.85

Publications

0 publications found

Variant links:

Genes affected

RPS6KA5 (HGNC:10434): (ribosomal protein S6 kinase A5) Enables ATP binding activity and protein serine/threonine kinase activity. Involved in several processes, including histone-serine phosphorylation; positive regulation of histone modification; and regulation of transcription, DNA-templated. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

RPS6KA5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.791

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004755.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RPS6KA5	NM_004755.4	MANE Select	c.458A>T	p.Glu153Val	missense	Exon 4 of 17	NP_004746.2
RPS6KA5	NM_001322229.2		c.458A>T	p.Glu153Val	missense	Exon 4 of 17	NP_001309158.1
RPS6KA5	NM_001322236.2		c.458A>T	p.Glu153Val	missense	Exon 4 of 16	NP_001309165.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPS6KA5	ENST00000614987.5	TSL:1 MANE Select	c.458A>T	p.Glu153Val	missense	Exon 4 of 17	ENSP00000479667.1	O75582-1
RPS6KA5	ENST00000418736.6	TSL:1	c.458A>T	p.Glu153Val	missense	Exon 4 of 13	ENSP00000402787.2	O75582-2
RPS6KA5	ENST00000554206.1	TSL:1	n.458A>T		non_coding_transcript_exon	Exon 4 of 10	ENSP00000450591.1	G3V2D1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460682

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39636

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111018

Other (OTH)

AF:

0.00

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.34

PhyloP100

5.9

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.63

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.72

MutPred

0.59

Gain of catalytic residue at I156 (P = 8e-04)

MVP

0.84

ClinPred

0.98

GERP RS

5.3

Varity_R

0.58

gMVP

0.84

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over